Sertoli cells modulate testicular vascular network development, structure, and function to influence circulating testosterone concentrations in adult male mice

Rebourcet, D. et al. (2016) Sertoli cells modulate testicular vascular network development, structure, and function to influence circulating testosterone concentrations in adult male mice. Endocrinology, 157(6), pp. 2479-2488. (doi: 10.1210/en.2016-1156) (PMID:27145015) (PMCID:PMC4891787)

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Abstract

The testicular vasculature forms a complex network, providing oxygenation, micronutrients, and waste clearance from the testis. The vasculature is also instrumental to testis function because it is both the route by which gonadotropins are delivered to the testis and by which T is transported away to target organs. Whether Sertoli cells play a role in regulating the testicular vasculature in postnatal life has never been unequivocally demonstrated. In this study we used models of acute Sertoli cell ablation and acute germ cell ablation to address whether Sertoli cells actively influence vascular structure and function in the adult testis. Our findings suggest that Sertoli cells play a key role in supporting the structure of the testicular vasculature. Ablating Sertoli cells (and germ cells) or germ cells alone results in a similar reduction in testis size, yet only the specific loss of Sertoli cells leads to a reduction in total intratesticular vascular volume, the number of vascular branches, and the numbers of small microvessels; loss of germ cells alone has no effect on the testicular vasculature. These perturbations to the testicular vasculature leads to a reduction in fluid exchange between the vasculature and testicular interstitium, which reduces gonadotropin-stimulated circulating T concentrations, indicative of reduced Leydig cell stimulation and/or reduced secretion of T into the vasculature. These findings describe a new paradigm by which the transport of hormones and other factors into and out of the testis may be influenced by Sertoli cells and highlights these cells as potential targets for enhancing this endocrine relationship. The testicular vasculature forms a complex capillary bed, interdigitating between the seminiferous tubules to provide oxygenation, delivery of micronutrients, and clearance of waste from the testis. Impairment of the testicular vasculature, for example, the reduction in venous drainage observed in cases of varicocele, causes intratesticular hypoxia and germ cell apoptosis (1). The vasculature is also instrumental to the endocrine function of the testis because it is the route by which pituitary gonadotropins are delivered to the testis to support T production and spermatogenesis (2). Conversely, alongside the lymphatic system, the vascular system is important for transport of T to other body systems; a reduced testis and vascular volume is associated with a reduction in circulating T concentrations (3). Our understanding of the mechanisms by which the testis controls local vascular function in adulthood is extremely limited. There is some evidence that testicular mast cells can influence vascular blood flow through release of 5-hydroxytryptamine (4), but perhaps the most well-studied factor influencing testicular vascular function is T. T is a well-established regulator of testicular vasomotion (rhythmical contraction and relaxation of blood vessels, independent of heartbeat) (5, 6) via direct T-mediated activation of the androgen receptor in smooth muscle cells of the testicular vasculature (7). Speculation that Sertoli cells may influence the testicular vasculature is supported by some indirect evidence (5) and in vitro studies (8), but confirmation of a direct role for Sertoli cells in the regulation of the testicular vasculature in vivo has never been demonstrated unequivocally. Recently we developed a unique model system that uses diphtheria toxin to specifically and acutely ablate Sertoli cells from the testis (9, 10). This model has revealed several important, yet previously unknown, roles that Sertoli cells play in neonatal and adult life (reviewed in reference 11). In this study we used models of acute Sertoli cell ablation and acute germ cell ablation, to address whether Sertoli cells actively influence vascular function in the adult testis. Our findings suggest that Sertoli cells play a key role in supporting the structure of the testicular vasculature and describe a new paradigm by which the transport of hormones and other factors into and out of the testis can be influenced by Sertoli cells and highlights these cells as potential targets for enhancing this endocrine relationship.

Item Type:Articles
Additional Information:This work was supported by Biotechnology and Biological Sciences Research Council Project Grant BB/J015105/1 (to L.B.S. and P.J.O.) and a Medical Research Council Program Grant Award MR/N002970/1 (to L.B.S.).
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:O'Shaughnessy, Professor Peter
Authors: Rebourcet, D., Wu, J., Cruickshanks, L., Smith, S. E., Milne, L., Fernando, A., Wallace, R. J., Gray, C. D., Hadoke, P. W. F., Mitchell, R. T., O'Shaughnessy, P. J., and Smith, L. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
Journal Name:Endocrinology
Publisher:Endocrine Society
ISSN:0013-7227
ISSN (Online):1945-7170
Published Online:04 May 2016
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Endocrinology 157(6):2479-2488
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
694851Androgens: unlocking the key drivers of male health and wellbeingColin SelmanMedical Research Council (MRC)MR/N002970/1RI BIODIVERSITY ANIMAL HEALTH & COMPMED